Polysaccharide-Based Drug Delivery Systems in Pediatrics: Addressing Age-Specific Challenges and Therapeutic Applications

Abstract

Pediatric drug delivery presents unique challenges due to physiological and pharmacological differences across age groups, requiring specialized formulation approaches beyond simple dose adjustments of adult medications. This review synthesizes recent advances in polysaccharide-based pediatric drug delivery and highlights novel findings that may accelerate clinical translation. It summarizes how chitosan, alginate, hyaluronic acid, dextran, modified starches, and other polysaccharides are engineered into nanoparticles, hydrogels, films, and orodispersible/mini-tablet formulations to improve stability, bioavailability, taste masking, and controlled release across neonates to adolescents. These systems can accommodate developmental variations in absorption, distribution, metabolism, and excretion processes across pediatric subpopulations, with particular emphasis on oral and alternative administration routes. Evidence supporting unexpectedly high acceptability of mini-tablets, successful integration of modified polysaccharides in 3D-printed personalized low-dose therapies, and the emergence of blood–brain barrier-penetrating and RGD-functionalized polysaccharide nanocarriers for pediatric oncology are emphasized as novel, clinically relevant trends. This review also addresses regulatory considerations, safety profiles, and future perspectives. By integrating developmental insights with innovative formulation strategies, polysaccharide polymers offer promising solutions to improve medication adherence, safety, and efficacy across the pediatric age spectrum.

1. Introduction

Pediatric drug delivery represents a complex and evolving field that faces unique challenges distinct from adult medicine. Children are not simply “small adults,” but rather a heterogeneous population with substantial physiological differences that change dramatically throughout development [1,2]. These differences significantly impact drug absorption, distribution, metabolism, and excretion processes, necessitating specialized formulation approaches beyond simple dose adjustments of adult drugs [3,4]. Despite increased regulatory attention and scientific advancement in recent decades, there remains a significant gap in age-appropriate formulations designed specifically for pediatric patients [5,6].

The oral route remains the most preferred administration pathway for pediatric patients due to its ease of administration and non-invasive nature [7]. However, conventional oral formulations present numerous challenges in pediatric populations. Liquid formulations, while traditionally favored for younger children, often require taste-masking agents, preservatives, and solubilizers that may pose safety concerns [8,9]. Additionally, these formulations frequently lack controlled-release capabilities, necessitating multiple daily doses that can reduce adherence [10]. Solid dosage forms, particularly mini-tablets and orodispersible formulations, have emerged as promising alternatives that combine the stability and dosing precision with improved acceptability across various age groups [11,12,13].

Polysaccharide polymers have gained significant attention as versatile biomaterials for addressing these pediatric-specific challenges [14,15]. These natural biopolymers (Table 1), including chitosan, alginate, dextran, cellulose derivatives, and various plant-derived polysaccharides, offer exceptional biocompatibility, biodegradability, and functional versatility for pharmaceutical applications [16,17]. Their inherent properties, such as mucoadhesion, pH-responsiveness, and ability to form various structures (nanoparticles, hydrogels, films), make them particularly valuable for developing age-appropriate drug delivery systems [18,19].

Table 1. Classification of Polysaccharides Used in Pediatric Drug Delivery Based on Origin.

The physiological differences across pediatric age groups present both challenges and opportunities for drug delivery innovation. Neonates and infants exhibit distinct gastrointestinal characteristics, including variable gastric pH, reduced digestive fluid volumes, and higher intestinal permeability compared to older children and adults [24,25,26]. These developmental variations influence drug solubility, stability, and absorption kinetics, requiring tailored formulation strategies [27,28]. Similarly, age-dependent changes in hepatic metabolism and renal excretion significantly impact drug pharmacokinetics and necessitate careful consideration in delivery system design [29,30].

Polysaccharide-based delivery systems offer promising solutions to these challenges through various mechanisms. For instance, chitosan’s mucoadhesive properties and ability to temporarily open epithelial tight junctions can enhance the absorption of poorly bioavailable drugs across the intestinal mucosa [31]. Alginate-based formulations provide pH-responsive release profiles that can protect acid-labile drugs from gastric degradation while enabling controlled release in the intestinal environment [16]. Furthermore, the versatility of polysaccharides allows for the development of various pediatric-friendly dosage forms, including orodispersible films (ODFs), mini-tablets, and chewable formulations that improve acceptability and compliance [32,33].

Beyond oral delivery, polysaccharide polymers have demonstrated significant potential in alternative administration routes relevant to pediatric care (Table 2). These include nasal delivery systems for vaccines and central nervous system-targeted therapies [34,35] transdermal formulations that leverage the enhanced permeability of neonatal and infant skin [36], and targeted delivery platforms for pediatric oncology applications [37]. The latter is particularly significant given the long-term adverse effects associated with conventional chemotherapy in developing tissues and organs [38,39].

Recent advances in polysaccharide modification techniques, including chemical derivatization, crosslinking, and conjugation, have further expanded the functional capabilities of these biopolymers [40,41,42,43]. These modifications enable precise control over properties such as solubility, degradation rate, and drug release kinetics, allowing for the development of increasingly sophisticated delivery systems tailored to pediatric needs [44]. Additionally, the emergence of nanotechnology has opened new avenues for polysaccharide-based formulations, offering improved drug stability, enhanced cellular uptake, and potential for targeted delivery [45,46,47]. However, it is important to approach nanotechnology carefully and ensure the responsible use of nanocarriers for children [45]. Regulatory guidelines emphasize the use of only well-validated, GRAS excipients (Generally Recognized as Safe) and avoidance of toxic solvents or adjuvants in pediatric formulations, and nanoparticles are generally engineered at ~100–150 nm to prevent capillary blockage. To date, few polymeric nanoformulations have advanced to pediatric trials (mostly for oncology), underscoring the need for dedicated pediatric PK/toxicity studies. In practice, each polymeric carrier must demonstrate age-appropriate safety before it can be used clinically. Overall, available evidence suggests that biodegradable polymeric nanoparticles have favorable biocompatibility, but long-term pediatric safety must be confirmed case-by-case under stringent regulatory oversight [46,47].

Despite these promising developments, several challenges remain in translating polysaccharide-based delivery systems to clinical pediatric applications. These include manufacturing scalability, regulatory considerations specific to pediatric formulations, and the need for comprehensive safety and efficacy data across different age groups [48]. Furthermore, the biological heterogeneity of pediatric populations necessitates careful consideration of age-appropriate dosing strategies and potential age-dependent variations in response to these delivery systems [49].

This review aims to provide a comprehensive analysis of polysaccharide-based drug delivery systems in pediatric applications, examining their potential to address age-specific challenges and enhance therapeutic outcomes. We explore the fundamental characteristics of various polysaccharide polymers, their formulation into different dosage forms, and their applications across diverse pediatric conditions. Special emphasis is placed on how these delivery systems can be tailored to accommodate the physiological and pharmacological differences across pediatric age groups, from neonates to adolescents. By integrating physiological understanding with innovative formulation strategies, this review seeks to highlight the significant potential of polysaccharide polymers in advancing pediatric drug delivery and improving medication safety, efficacy, and acceptability for this vulnerable patient population.

2. Formulation Trends and Acceptability in Pediatric Drug Delivery

Recent developments in pediatric drug delivery have emphasized the requirement for dosage forms that are age-appropriate and suited to the physiological and developmental needs of children. These formulations must meet high standards of acceptability and safety while allowing for flexible, accurate dosing to accommodate individual therapeutic needs. They also require child-safe excipients, pleasant taste and texture, and compliance with regulatory guidelines [5,6]. The ICH E11(R1) guideline on clinical investigation of medicinal products in pediatric populations requires that excipient selection be scientifically justified, as children display age-dependent physiological differences such as immature metabolic pathways and organ function, which may increase sensitivity to excipient-related toxicity [50]. The European Medicines Agency (EMA) also issues regulatory guidance that underscores the importance of developing age-appropriate formulations and justifying excipient choices based on pediatric safety data. These frameworks collectively recommend minimizing both the number and quantity of excipients, and ensuring that each excipient in a pediatric formulation is supported by a risk–benefit assessment tailored to the intended age group [51].

Additionally, the Safety and Toxicity of Excipients for Pediatrics (STEP) database offers an updated repository of clinical, non-clinical, and regulatory information on excipient use in children [52]. These resources facilitate evidence-based decision-making by enabling researchers to identify excipients with established pediatric tolerability, recognize age groups at elevated risk, and avoid excipients with documented toxicities or insufficient safety data. Early integration of these tools in formulation development is essential to ensure both the safety and regulatory compliance of pediatric drug products.

Oral pediatric formulations (Figure 1) are available in various formats—including liquids (e.g., syrups, suspensions, elixirs) and solids (e.g., tablets, capsules, chewable tablets, powders, and orodispersible forms) [6]. One of the primary challenges in pediatric formulation is selecting the most suitable dosage form for each age group. While liquid formulations are typically favored for younger children who may struggle with swallowing solids, emerging evidence suggests that this approach may not always be optimal. For instance, tablets have traditionally been considered inappropriate for children under six years old [53]. However, a study of 55 children aged 4–12 years showed that even children as young as four could successfully swallow tablets, with some even preferring them [11]. Mini-tablets, typically 2 to 4 mm in diameter, have demonstrated surprising acceptability, even in children under two years old and neonates, but evidence is currently limited, and uncertainties remain regarding larger sizes, multiple-unit dosing, and use in children with medical conditions. Klingmann [12] reported that mini-tablets were more acceptable than syrup in all pediatric age groups (Figure 2). These findings have contributed to the World Health Organization’s call for a transition from liquid to solid dosage forms and have influenced regulatory perspectives in the European Union [12]. Further research from the Netherlands comparing the acceptability of different oral forms, mini-tablets, syrups, suspensions, and powders, found mini-tablets to be most favored by both children and their caregivers [13]. These findings support the broader shift toward solid dosage forms in pediatric medicine, which offer several key advantages: better taste masking, more accurate dosing, improved stability, and fewer harmful excipients compared to liquids.

Although liquid medications are widely used, they pose challenges such as masking unpleasant tastes, ensuring accurate dosing, and avoiding potentially harmful excipients that may cause allergic reactions, central nervous system disturbances, or jaundice. Common examples of these excipients include ethanol, propylene glycol, polyoxyl castor oil, polysorbate 80, parabens, benzyl alcohol, benzoic acid, sodium metabisulfites, saccharin, aspartame, glucose, sucrose, and sorbitol [8]. Liquids also often require refrigeration, have shorter shelf lives, and are more complex to package and store [9]. Additionally, most do not offer controlled-release options, often necessitating multiple daily doses and reducing adherence [10]. In contrast, solid forms, especially mini-tablets, provide a more stable, cost-effective, and patient-friendly alternative. Their small size allows for flexible dosing by adjusting the number of units administered, making them suitable across a wide age range [54]. The development of orally disintegrating mini-tablets (mini ODTs) has further advanced this field [6,55]. Mini ODTs not only retain the benefits of mini-tablets but also dissolve quickly in the mouth, allowing for buccal or sublingual absorption. This can bypass first-pass metabolism and lead to faster therapeutic effects. Alternatively, after disintegration, the drug may be swallowed for absorption via the gastrointestinal tract, offering multiple routes of delivery from a single dosage form [56].

These features make mini ODTs especially valuable for younger children and those with swallowing difficulties, effectively combining the flexibility of liquids with the stability and precision of solids. As such, they are increasingly recognized as a gold standard for age-appropriate formulations [57]. While challenges remain such as optimizing taste masking and achieving sustained-release profiles, the use of polysaccharide-based matrices in both mini ODTs and ODFs supports the development of child-friendly, adaptable drug delivery platforms suitable for oral and buccal administration [56].

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Račić, A.; Gatarić, B.; Topić Vučenović, V.; Stojmenovski, A. Polysaccharide-Based Drug Delivery Systems in Pediatrics: Addressing Age-Specific Challenges and Therapeutic Applications. Polysaccharides 2025, 6, 108. https://doi.org/10.3390/polysaccharides6040108

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